All existing forms of androgen deprivation therapy (ADT), the backbone of systemic prostate cancer (PCa) treatment, involve inhibition of either ligand production or ligand binding to the androgen receptor (AR). However, most of the patients with advanced PCa eventually progress into castration-refractory prostate cancer, for which there are no current cures. The principal cause of ADT failure is the selection for the forms of AR that no longer require androgen but remain active in regulating transcription of androgen-responsive genes and confer resistance to anti-androgens or testosterone synthesis inhibitors. Furthermore, the inhibition of AR not only suppresses AR-activated cancer-supporting genes but also induces other genes supporting cell proliferation, which are normally repressed by AR. Thus there is a need for therapies that (i) block AR-induced transcription but do not interfere with the inhibition of transcription by AR and (ii) act downstream of AR and should therefore be effective against its androgen-independent forms. We have now identified two closely related transcription-regulating kinases, CDK8 /19, as novel modulators of AR signaling that satisfy the above criteria. CDK8/19 inhibition suppresses AR-induced gene expression and cell proliferation in androgen- dependent and androgen-independent PCa models and inhibits other transcription factors implicated in PCa, such as MYC and NFkB. We have developed a first-in-class selective CDK8/19 inhibitor drug candidate, Senexin B, which is non-toxic, bioavailable both parenterally and orally, and active in various cancer models in vivo. We now propose to investigate the suitability of this compound for the treatment of advanced PCa. For this purpose, we will verify the tumor-suppressive effects of the CDK8/19 inhibitor Senexin B, observed in preliminary studies in a partially androgen-independent PCa model that expresses the full-length form of AR, determine if oral administration of Senexin B can be used in this model instead of the parenteral. The efficacy of Senexin B will be compared in intact and castrated mice, as an indication if CDK8/19 inhibition may be advantageously used in combination with ADT. We will also determine the efficacy of Senexin B in a fully androgen-independent xenograft model that expresses a splice variant of AR commonly found in human tumors. In addition, we will test the efficacy of Senexin B in a syngeneic murine PCa transplant model, proliferation of which is driven by MYC oncogene. Phase II of this project will comprise detailed analysis of the effects of Senexin B in different PCa models, comparison of the efficacy of Senexin B alone and in combinations with ADT and chemotherapy, and IND-enabling preclinical studies, required to start clinical trials of the first-in-class CDK8/19 inhibitor for he treatment of advanced PCa.